Moderate-to-severe psoriasis affects 1.5 million people in the U.S. Multiple, well-designed, population-based observational studies provide convincing evidence that psoriasis is associated with 1.5- to 2-fold increased risk for cardiovascular and metabolic complications. However, the effect of immunomodulatory therapy on risk has not been adequately evaluated. Nor has risk been evaluated with respect to intermediating physiologic measures. We propose to assess the comparative effectiveness of immunomodulatory drugs used by patients with moderate-to-severe psoriasis for improving body mass index, blood pressure, lipids, and fasting plasma glucose. If these physiologic measures are worsened in psoriasis but are substantially resistant to immunomodulatory therapy, then those at high risk should be identified for screening and early behavioral intervention. On the other hand, if immunomodulatory therapy for psoriasis improves or worsens these measures, then evidence is urgently needed by doctors and patients to make sound treatment decisions that balance benefits against risks and costs given the patient's personal risk profile. The drugs under study will include anti-TNF agents, methotrexate, oral retinoids and cyclosporine. Risk on these drugs will be compared to risk on phototherapy without systemic agent. The number of patients eligible for the study is 8385, with ample numbers having exposure to the study drugs (anti-TNF, methotrexate, oral retinoids, and cyclosporine) and comparison therapy. Because the focus is on physiologic measures, the study has substantial power for subgroup analysis, with the goal of selecting patients for personalized therapy. The study will provide information that can be translated immediately and directly to the clinical setting so that doctors and patients can make the best treatment choices given the patient's underlying risk for cardiovascular disease and diabetes. We have estimated the potential impact of the study using conservative assumptions. If optimizing drug therapy reduces risk by even 5%, then 40,000 cases of cardiovascular disease and diabetes could be prevented. Alternatively, the study could demonstrate no benefit of anti-TNF therapy on physiologic risk factors for cardiovascular disease and diabetes, in which case the value of anti-TNF therapy could be optimized by maintaining valid, tight prescribing indications. The study could also inform study design and future assessments of the indirect benefits of specialty pharmaceuticals.